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Transforming the Degradation Rate of β-tricalcium Phosphate Bone Replacement Using 3-Dimensional Printing

Shen, Chen; Wang, Maxime M; Witek, Lukasz; Tovar, Nick; Cronstein, Bruce N; Torroni, Andrea; Flores, Roberto L; Coelho, Paulo G
BACKGROUND:β-Tricalcium phosphate (β-TCP) is one of the most common synthetic bone grafting materials utilized in craniofacial reconstruction; however, it is limited by a slow degradation rate. The aim of this study was to leverage 3-dimensional (3D) printing in an effort to accelerate the degradation kinetics of β-TCP. METHODS:Twenty-two 1-month-old New Zealand white rabbits underwent creation of calvarial and alveolar defects, repaired with 3D-printed β-TCP scaffolds coated with 1000 μM of osteogenic agent dipyridamole. Rabbits were euthanized after 2, 6, and 18 months after surgical intervention. Bone regeneration, scaffold degradation, and bone mechanical properties were quantified. RESULTS:Histological analysis confirmed the generation of vascularized and organized bone. Microcomputed tomography analysis from 2 to 18 months demonstrated decreased scaffold volume within calvarial (23.6% ± 2.5%, 5.1% ± 2.2%; P < 0.001) and alveolar (21.5% ± 2.2%, 0.2% ± 1.9%; P < 0.001) defects, with degradation rates of 54.6%/year and 90.5%/year, respectively. Scaffold-inducted bone generation within the defect was volumetrically similar to native bone in the calvarium (55.7% ± 6.9% vs 46.7% ± 6.8%; P = 0.064) and alveolus (31.4% ± 7.1% vs 33.8% ± 3.7%; P = 0.337). Mechanical properties between regenerated and native bone were similar. CONCLUSIONS:Our study demonstrates an improved degradation profile and replacement of absorbed β-TCP with vascularized, organized bone through 3D printing and addition of an osteogenic agent. This novel additive manufacturing and tissue engineering protocol has implications to the future of craniofacial skeletal reconstruction as a safe and efficacious bone tissue engineering method.
PMCID:8616850
PMID: 34611100
ISSN: 1536-3708
CID: 5072082

Self-assembling human skeletal organoids for disease modeling and drug testing

Abraham, Diana M; Herman, Calvin; Witek, Lukasz; Cronstein, Bruce N; Flores, Roberto L; Coelho, Paulo G
Skeletal conditions represent a considerable challenge to health systems globally. Barriers to effective therapeutic development include a lack of accurate preclinical tissue and disease models. Most recently, work was attempted to present a novel whole organ approach to modeling human bone and cartilage tissues. These self-assembling skeletal organoids mimic the cellular milieu and extracellular organization present in native tissues. Bone organoids demonstrated osteogenesis and micro vessel formation, and cartilage organoids showed evidence of cartilage development and maturation. Skeletal organoids derived from both bone and cartilage tissues yielded spontaneous polarization of their cartilaginous and bone components. Using these hybrid skeletal organoids, we successfully generated "mini joint" cultures, which we used to model inflammatory disease and test Adenosine (A2A ) receptor agonists as a therapeutic agent. The work and respective results indicated that skeletal organoids can be an effective biological model for tissue development and disease as well as to test therapeutic agents.
PMID: 34837719
ISSN: 1552-4981
CID: 5063982

Double Frost Suture Technique for Simultaneous Skin Grafting of the Upper and Lower Eyelids

DeMaria, Lauren N; Tran, Ann Q; Tooley, Andrea A; North, Victoria S; Flores, Roberto L; Lisman, Richard D; Belinsky, Irina
The double Frost suture is a useful supplement to the reconstruction of ipsilateral upper and lower eyelid defects with full-thickness skin grafts. This technique involves silk traction sutures that overlap the upper and lower eyelids to place them on maximal stretch after placement of 2 full-thickness skin grafts. It has the added benefit of protecting the cornea and compressing both grafts under 1 bolster. The authors illustrate this technique in 2 pediatric cases-a congenital melanocytic kissing eyelid nevus and a periocular burn. Each case resulted in large upper and lower anterior lamellar defects, which were reconstructed with supraclavicular and retroauricular free skin grafts. The double Frost sutures counter vertical cicatricial forces during graft healing, obviating the need for staged procedures. Both described cases resulted in excellent graft survival with minimal contracture.
PMID: 34297708
ISSN: 1537-2677
CID: 4948712

The Surgical Treatment of Robin Sequence: Neonatal Mandibular Distraction Osteogenesis in the Unfavorable Patient

Shen, Chen; Wang, Maxime M; Eisemann, Bradley T; Rodriguez, Alcibiades J; Rickert, Scott M; Flores, Roberto L
INTRODUCTION/BACKGROUND:Neonates with severe Pierre Robin sequence (PRS) can be treated by mandibular distraction osteogenesis (MDO), tongue-lip adhesion, or tracheostomy; however, there is an active debate regarding the indications of MDO in this patient population. Published algorithms identify tracheomalacia, bronchomalacia, laryngomalacia, hypotonic syndromes, and central sleep apnea as contraindications for MDO and indications for tracheostomy, but these comorbidities may exist along a spectrum of severity. The authors propose that appropriately selected neonates with PRS who concurrently express 1 or more of these traditional contraindications may be successfully treated with MDO. METHODS:The authors performed a 5-year retrospective chart review of all neonates who underwent MDO for treatment of severe PRS. All patients expressed a comorbidity previously identified as an indication for tracheostomy. Pre- and postoperative characteristics were recorded. Apnea/hypopnea index (AHI) before and after MDO were compared using 2-tailed repeated measures t-test. RESULTS:The authors identified 12 patients with severe PRS and conditions associated with contraindications to MDO: 9 (75.0%) patients had laryngomalacia, 6 (50.0%) patients had tracheomalacia, 2 (16.6%) patients had bronchomalacia, 1 (8.3%) patient had central sleep apnea, and 3 (25.0%) patients had hypotonia. Five (41.7%) patients underwent concurrent gastrostomy tube placement due to feeding insufficiency. Average birthweight was 3.0 kg. Average pre-op AHI was 34.8. Average post-op AHI was 7.3. All patients successfully underwent MDO with avoidance of tracheostomy. CONCLUSIONS:By employing an interdisciplinary evaluation of patient candidacy, MDO can safely and effectively treat upper airway obstruction and avoid tracheostomy in higher-risk neonatal patients with traditional indications for tracheostomy.
PMID: 34705382
ISSN: 1536-3732
CID: 5038922

Advantages and disadvantages of mandibular distraction in Robin sequence

Breugem, Corstiaan C; Logjes, Robrecht J H; Nolte, Jitske W; Flores, Roberto L
Robin sequence (RS) is diagnosed in infants born with micrognathia, glossoptosis and varying degrees of upper airway obstruction (UAO). Due to the variable levels of hypoxia, severe breathing and feeding problems can occur. Treatment is determined by clinical severity, ranging from conservative interventions for mild cases to surgical interventions for severe cases. Mandibular distraction osteogenesis (MDO) is a surgical technique that gradually lengthens the mandible after an osteotomy by using an internal or external distraction device, directly correcting the micrognathia. This review will focus on advantages and disadvantages of mandibular distraction in infants with RS.
PMID: 34663561
ISSN: 1878-0946
CID: 5043162

Skeletal and Dental Stability Following Different Magnitude of Le Fort I Advancement in Patients With Cleft Lip and Palate

Wangsrimongkol, Buddhathida; Flores, Roberto L; Staffenberg, David A; Rodriguez, Eduardo D; Shetye, Pradip R
PURPOSE/OBJECTIVE:The purpose of this study was to measure the association between the magnitude of advancement and dental and skeletal relapse in patients with cleft lip and palate (CLP). METHODS:A single-institution retrospective cohort study of skeletally matured patients with CLP who underwent isolated Le Fort I advancement surgery between 2013 and 2019 was studied. Patients were included if they had lateral cephalograms or cone-beam computed tomography (CBCT) at preoperative (T1), immediately postoperative (T2), and 1-year follow-up (T3). Lateral cephalometric landmarks were digitized and measured. The sample was divided on the basis of the magnitude of skeletal advancement: minor (<5 mm), moderate (≥5 but <10 mm), and major (≥10 mm) advancement groups. The mean advancement and relapse were compared between groups using 1-way ANOVA. Correlation between the amount of surgical advancement and relapse was evaluated. RESULTS:Forty-nine patients with nonsyndromic CLP with hypoplastic maxilla met inclusion criteria and the sample consisted of 36 males and 13 females with the mean age of 19.5 years. In the minor, moderate, and major advancement groups, the mean advancement at point A was +4.1 ± 0.4, + 7.5 ± 1.4, and +11.3 ± 1.3 mm, respectively. At 1-year follow-up, the mean relapse at point A was -1.3 ± 1.2, -1.1 ± 1.2, and -1.7 ± 1.5 mm, respectively. There was no significant difference in the relapse amount between all surgical groups. No correlation between the magnitude of advancement and relapse was found. CONCLUSIONS:This study demonstrated no statistically significant difference in skeletal stability between a minor (<5 mm), moderate (≥5 but <10 mm), and major (≥10 mm) Le Fort I advancement groups in patients with clefts. Regardless of the degree of advancement, mild skeletal relapse was observed in all 3 groups.
PMID: 34153247
ISSN: 1531-5053
CID: 4918192

Objective measurements for upper airway obstruction in infants with Robin sequence: what are we measuring? A systematic review

Logjes, Robrecht J H; MacLean, Joanna E; de Cort, Noor W; Poets, Christian F; Abadie, Véronique; Joosten, Koen F M; Resnick, Cory M; Trindade-Suedam, Ivy K; Zdanski, Carlton J; Forrest, Christopher R; Kruisinga, Frea H; Flores, Roberto L; Evans, Kelly N; Breugem, Corstiaan C
STUDY OBJECTIVES/OBJECTIVE:Identifying optimal treatment for infants with Robin sequence (RS) is challenging due to substantial variability in the presentation of upper airway obstruction (UAO) in this population. Objective assessments of UAO and treatments are not standardized. A systematic review of objective measures of UAO was conducted as step towards evidence based clinical decision making for RS. METHODS:A literature search was performed in Pubmed and Embase databases (1990-2020) following PRISMA-guidelines. Articles reporting on RS and UAO-treatment were included if the following objective measures were studied: oximetry, polysomnography and blood gas. Quality was appraised by methodological index for non-randomized studies (MINORS, range:0-24). RESULTS:A total of 91 articles met inclusion criteria. Mean MINORS-score was 7.1 (range:3-14). Polysomnography was most frequently used (76%) followed by oximetry (20%) and blood gas (11%). Sleep position of the infant was reported in 35% of studies, with supine position most frequently, and monitoring time in 42%, including overnight recordings in more than half. Of 71 studies that evaluated UAO-interventions, the majority used polysomnography (90%), of which 61% did not specify the polysomnography technique. Reported polysomnography metrics included oxygen saturation (61%), apnea-hypopnea index (52%), carbon dioxide levels (31%), obstructive-apnea-hypopnea index (27%), and oxygen-desaturation-index (16%). Only 42 studies reported indications for UAO-intervention, with oximetry and polysomnography thresholds used equally (both 40%). In total, 34 distinct indications for treatment were identified. CONCLUSIONS:This systematic review demonstrates a lack of standardization, interpretation and reporting of assessment and treatment indications for UAO in RS. An international, multidisciplinary consensus protocol is needed to guide clinicians on optimal UAO assessment in RS.
PMID: 33960296
ISSN: 1550-9397
CID: 4874112

Perceived Barriers to Comprehensive Cleft Care Delivery: Results From A Capacity-Building Educational Initiative and Implications

Kantar, Rami S; Breugem, Corstiaan C; Alfonso, Allyson R; Keith, Kristen; Kassam, Serena; Annan, Beyhan; Chahine, Elsa M; Wasicek, Philip J; Patel, Krishna G; Flores, Roberto L; Hamdan, Usama S
INTRODUCTION:We analyzed the perceptions of participants and faculty members in simulation-based comprehensive cleft care workshops regarding comprehensive cleft care delivery in developing countries. METHODS:Data were collected from participants and faculty members in 2 simulation-based comprehensive cleft care workshops organized by Global Smile Foundation. We collected demographic data and surveyed what they believed was the most significant barrier to comprehensive cleft care delivery and the most important intervention to deliver comprehensive cleft care in developing countries. We also compared participant and faculty responses. RESULTS:The total number of participants and faculty members was 313 from 44 countries. The response rate was 57.8%. The majority reported that the most significant barrier facing the delivery of comprehensive cleft care in developing countries was financial (35.0%), followed by the absence of multidisciplinary cleft teams (30.8%). The majority reported that the most important intervention to deliver comprehensive cleft care was creating multidisciplinary cleft teams (32.2%), followed by providing cleft training (22.6%). We found no significant differences in what participants and faculty perceived as the greatest barrier to comprehensive cleft care delivery (P = 0.46), or most important intervention to deliver comprehensive cleft care in developing countries (P = 0.38). CONCLUSIONS:Our study provides an appraisal of barriers facing comprehensive cleft care delivery and interventions required to overcome these barriers in developing countries. Future studies will be critical to validate or refute our findings, as well as determine country-specific roadmaps for delivering comprehensive cleft care to those who need it the most.
PMID: 34253700
ISSN: 1536-3708
CID: 4968782

Craniosynostosis: Le Fort III Distraction Osteogenesis

Mittermiller, Paul A; Flores, Roberto L; Staffenberg, David A
The Le Fort III advancement was first described in 1950 and has since become a key technique in the armamentarium of craniofacial surgeons. The application of distraction osteogenesis to the craniofacial skeleton has allowed for large movements to be performed safely in young patients. This technique is valuable for correcting exorbitism, airway obstruction owing to midface retrusion, and class III malocclusion. It can be performed with either an external distractor or internal distractors. Although serious complications have been reported, these occur rarely when performed by experienced providers.
PMID: 34051899
ISSN: 1558-0504
CID: 4890662

Robin Sequence: Neonatal Mandibular Distraction

Morrison, Kerry A; Collares, Marcus V; Flores, Roberto L
Pierre Robin sequence is defined by the clinical triad: mandibular hypoplasia, glossoptosis, and airway obstruction. Mandibular distraction osteogenesis (MDO) is a standard treatment of Robin sequence associated with severe airway obstruction and is the only intervention that directly corrects the underlying anatomic pathologic condition. Compared with tongue-lip adhesion, MDO has demonstrated more success in treating airway obstruction in infants with Pierre Robin sequence, including patients with syndromic diagnoses and concomitant anomalies. This article provides a current, comprehensive review of neonatal mandibular distraction and offers treatment guidelines based on a combined surgical experience of more than 400 patients.
PMID: 34051891
ISSN: 1558-0504
CID: 4898182